1. Field
The present invention relates generally to fibrin glue, also known as tissue adhesive or fibrin sealant. More specifically, the invention relates to a delivery system which permits contact of a fibrinogen-containing solution with thrombin to form polymerizable fibrin prior to delivery of the solution to a site.
2. Background
Fibrin glues have been known for many years. For example, U.S. Pat. No. 2,533,004 to Ferry shows the use of varying concentrations of fibrinogen solution in conjunction with a thrombin solution for forming fibrin clots.
In addition to its principal ingredients, .alpha.-thrombin and fibrinogen, fibrin glue may contain a small amount of factor XIII, which co-purifies with the fibrinogen when purified from human plasma. In the presence of thrombin, soluble fibrinogen is converted into soluble fibrin which self-polymerizes into an insoluble matrix. Thrombin also converts factor XIII into factor XIIIa. The latter cross-links the fibrin matrix to give a highly crosslinked polymer, which contributes to the effectiveness of the tissue adhesive or fibrin glue. The adhesive preparations allow for reliable stopping of bleeding, make for good adhering capacity to the wound or tissue surfaces, provide for high straining capacity of the glued sites or sealed wounds, and provide for complete absorbability of the tissue adhesive in the course of wound healing. Fibrin glues have been used for control of bleeding (hemostasis), for augmentation or replacement of sutures or wound clips, for adhering skin grafts, for sealing puncture wounds, for sealing and adhering catheters, and even for use as a depot for drug delivery.
The fibrinogen and .alpha.-thrombin must be formulated in a manner that stabilizes and completely separates these two proteins until the time of their actual use. Because .alpha.-thrombin is an activated protease, it is particularly difficult to store stably in solution. U.S. Pat. Nos. 4,298,598 and 4,377,572 to Schwartz et al. and 4,909,251 to Seelich, e.g., show examples of compositions of fibrin glue preparations.
Existing commercial formulations for fibrin glue include separated frozen or lyophilized preparations of .alpha.-thrombin and fibrinogen prepackages in a dual syringe. The frozen formulations require that the product's two ingredients be stored and shipped in the frozen state. Finally, the dual syringe used to dispense existing fibrin glues is somewhat bulkier and more difficult to handle than a conventional syringe and may feel awkward to use.
Various types of applicators are disclosed in the prior art. For example, U.S. Pat. No. 4,359,049 to Redl discloses a syringe-type apparatus which includes a plurality of syringe bodies and a connecting head with a single needle.
An improved design applicator was disclosed in U.S. Pat. No. 4,974,368 to Miller. This applicator includes a pair of syringe tubes which can be actuated together or separately, a member which holds the syringes parallel to each other, and a double needle assembly which allows separate delivery of the components of the fibrin glue to the treatment site.
Another device uses syringes with barrels having different cross-sectional area, thus altering the relative quantities of the components. See U.S. Pat. No. 4,735,616 to Eibl which shows one syringe cross section having an area 2 to nine times larger then the second syringe.
Single-syringe fibrin sealants have been described. For example, in one application a mixture of fibrinogen and prothrombin is contained in a single syringe and clot formation occurs by action of endogenous factor Xa at the wound site. See also patents for light-reversible, inhibited thrombin together with fibrinogen (U.S. Pat. Nos. 5,219,328 and 5,318,524, both to McNally et al.; PCT/U.S. 91/00003).
At the 1995 Thrombosis and Hemostasis Meeting, there were two reports (Abstract Nos. 2150 and 2174) of novel fibrin monomer formulations which could be envisioned as a single-syringe glue. Batroxobin was used instead of thrombin to form soluble fibrin monomers and batroxobin was then removed by affinity chromatography. However, batroxobin, in contrast to thrombin, cleaves only fibrinopeptide A from fibrinogen and does not cleave fibrinopeptide B from fibrinogen or activate factor XIII.
U.S. Pat. No. 5,393,666 to Linnau discloses a method of activating prothrombin by means of trypsin, wherein the prothrombin is treated with trypsin immobilized on a water insoluble carrier and then is separated from the immobilized trypsin after activation.
A principal challenge in designing a single-syringe delivery system for fibrin glue is the need to separate completely the solution of fibrinogen from an activating protease, most preferably .alpha.-thrombin, until the moment of the use of the fibrin glue. With solutions of fibrinogen and thrombin, fibrin glue can only be generated in a controlled manner by using a dual-syringe system that effectively separates the fibrinogen from its activating protease until the desired time of glue generation.
To the best of our knowledge, no one has previously proposed the use of an immobilized protease cartridge, for attachment to a syringe tip, to activate fibrinogen and to thereby allow the delivery of the activated solution of polymerizable fibrin with a single syringe.